Simple reaction makes the building blocks of a nucleic acid

"Cyanide to the RNA base cytosine" becomes a new clue for origin of life researchers.

Origin-of-life researchers face a deceptively straightforward question: how did simple chemicals produce complex biochemistry? The complexity of this starts to come in when you consider the many complex biomolecules that would have been useful or essential to the first biochemical reactions. And it gets worse when you consider that there are lots of simple organic chemicals that plausibly could have been present on the early Earth. Figuring out which reactions to even start looking at can be a real challenge.

The extent of that challenge was highlighted a few years back, when a Cambridge lab suggested most earlier researchers had gone down a dead end. Previously, researchers tried to build up a sugar and a nucleic acid base separately, and then link to them to form precursors of DNA and RNA. But the group from Cambridge showed it was possible to build relatively simple compounds into a three-ring chemical that could then be converted into cytosine, an RNA component. Now, they've revisited that work and shown that all of the precursors of that reaction can be made with little more than cyanide.

The reaction the group reported back in 2009 only required a set of two or three carbon precursors, but these molecules were already somewhat complex: cyanamide, cyanoacetylene, glycolaldehyde, and glyceraldehyde. We don't know that all of these chemicals would be common on a pre-biotic Earth, which leaves its relevance to the origin of life a somewhat open question.

In a new paper, the same lab tackles forming the simple, two- and three-atom sugars used in their earlier work (glycolaldehyde and glyceraldehyde). To get there, they started with nothing more complex than hydrogen cyanide, a simple molecule comprised of one atom each of hydrogen, carbon, and nitrogen. Hydrogen cyanide forms readily under a variety of conditions, and has been found on several bodies in our Solar System, as well as in the interstellar medium.

The authors were intrigued by reports in the literature of a cycle that involves a set of six cyanide molecules, coordinated by two copper atoms. In a water solution, this complex can cycle, driven by ultraviolet light, through a set of reactions that alternately spit out cyanide, protons, and electrons. These electrons get temporarily attached to water molecules, and typically end up being taken up by a scavenger molecule, usually nitrate. However, some reports in the literature noted that, when nitrate isn't added to the reaction, some undefined larger molecules formed.

The authors went back and checked these reaction products, and found that they included both glycolaldehyde and glyceraldehyde—the two chemicals that were key building blocks of the reaction that produced the RNA precursor. And all the reaction required was copper ions and some UV light.

If left to continue cycling, the products of the reaction also included some more complex, five-atom ringed structures that incorporate nitrogen and oxygen in the ring. But the authors suspect that with the right conditions—namely the ones identified in the earlier paper—the products of this new cycle could be sent directly on to form cytosine. They also suggest the addition of other metals could shift the products to additional chemicals that may have biological relevance.

Hopefully, it's safe to assume the lab already has these projects in the works.

De novo synthesis of nucleotides occurs in the liver, which seems to be somewhat understood. Whats the purpose of trying to find an alternative method? Shouldn't the search revolve around a more primitive method based on the method already used by living organisms?

A question I ask myself all the time, "What came first, the ribosome or the DNA sequences that code for it?".

A question I ask myself all the time, "What came first, the ribosome or the DNA sequences that code for it?".

Probably the ribosome - see RNA World. The methods of peptidogenesis we see in mammals to day are sitting at the end of many million years of evolution, and almost certainly are far more efficient than those responsible for the initial development of life.

De novo synthesis of nucleotides occurs in the liver, which seems to be somewhat understood. Whats the purpose of trying to find an alternative method? Shouldn't the search revolve around a more primitive method based on the method already used by living organisms?

What I think you're asking is why are they looking at any method by which biomolecules spontaneously form, rather than trying to find the theoretical origin of the current biosynthesis pathways. The answer is that whatever happens today need not bear any resemblance to what happened 3.5 billion years ago in the primordial soup. We don't have any records from the first few billion years of how life was organized on a chemical level. All the rocks from that age have been recycled back into the interior of the planet.

Organisms trapped in amber or dormant extremeophile organisms in rock, ice, or salt date back almost half a billion years, but nothing on earth dates from the time when we suspect biomolecules first arose in self-replicating structures. We can infer from DNA mutation rates, long-lived species, and other methods what the most likely ancient pathways are, but that doesn't get us very far back and it's all far too uncertain for us to say with any certainty how the first self-organizing biomolecules did their thing.

Since we don't know what to look for, scientists are looking for anything that is plausible. Even a plausible hypothesis deflates the counter-hypothesis, which is that life cannot have arisen on Earth through random natural processes.

The answer is that whatever happens today need not bear any resemblance to what happened 3.5 billion years ago in the primordial soup. We don't have any records from the first few billion years of how life was organized on a chemical level. All the rocks from that age have been recycled back into the interior of the planet.

While I understand what you're trying to say, that's not true. Rocks in Canada and Australia have been dated to approximately 4 billion years old. Fossils from 3.4 billion years were found in Australia last year.

The image that popped into my head is that the cyanide genesis idea is the bio-chemical equivalent of a million monkeys typing Shakespeare.

I guess that if there is enough dissolved metals in sea water and other run-off from the local geological formations, you could see similar things happening billions and billions (thanks Mr Sagan) of times and eventually the chemical products start getting more complex. Presumably there was more ultraviolet light back then.

When you get to the bottom of it all, biology is based on chemistry which is based on essentially atomic and molecular electronics (and probability). So we're just biological robots, maybe androids? Yeah I know, there's a big jump from the water puddle to current day.

(If that doesn't rile them up in the Bible-belt.....and they thought being descended from apes was unthinkable! As long as we're quiet, we won't wake them up.)

The image that popped into my head is that the cyanide genesis idea is the bio-chemical equivalent of a million monkeys typing Shakespeare.

I guess that if there is enough dissolved metals in sea water and other run-off from the local geological formations, you could see similar things happening billions and billions (thanks Mr Sagan) of times and eventually the chemical products start getting more complex. Presumably there was more ultraviolet light back then.

When you get to the bottom of it all, biology is based on chemistry which is based on essentially atomic and molecular electronics (and probability). So we're just biological robots, maybe androids? Yeah I know, there's a big jump from the water puddle to current day.

(If that doesn't rile them up in the Bible-belt.....and they thought being descended from apes was unthinkable! As long as we're quiet, we won't wake them up.)

Your Shakespearean monkeys have to produce the complete works in 6000 years.

A question I ask myself all the time, "What came first, the ribosome or the DNA sequences that code for it?".

Meh... They have already shown that you can take the chemicals thought to be rife on early Earth, put them into a large beaker and amino acids will start to form on their own and some RNA. They have also shown an engineered RNA that could replicate itself.

Given enough time and many random interactions, you are bound to get RNA that replicates itself. How long until DNA is accidentally created?

The age old hypothesis was that RNA would resolve the DNA-protein chicken-and-egg evolutionary pathway bottleneck problem.

And indeed the classical find was that

- RNA is at the core of the genetic machinery in the forms of messenger RNA assembling proteins by transfer RNA adapters with the help of the ribosome RNA machinery.- RNA is at the core of the protein-to-membrane transport machinery in the form of the signal recognition particle RNA.- RNA chemistry is at the core of integrated cellular metabolism in the form of adenosine triphosphate (ATP) and related energy currency cofactors.- RNA is at the core of the genetic storage in the form of stabler DNA, which is energetically demanding and need protein enzymatic capability to be produced. Indeed, DNA nucleotides is metabolically derived from RNA precursors.

Finally 2010 it was possible to use the phylogenetic record to reach back to the last ~ 50 % of the genetic clock time beyond today's cellular domains. Turns out the record goes through the DNA universal ancestor (~ 20 % clock proxy time) and throughout the whole RNA/protein world (~ 20 % clock proxy time) by way of whole genome protein fold methods. [Various papers, see for example "The evolution and functional repertoires of translation proteins following the origin of life", Goldman et al, Biol Dir 2010.]

I would also expect that the ENCODE results, that shows conserved short and long RNAs interspersed with other functions, may uncover more of the pure RNA world than the classical finds.

Earlier this year it became known that RNA is perhaps an order of magnitude more catalytic capable in the original terrestrial environments of anoxic and iron filled environments. It was earlier known that enthalpic enzymes, like generic RNA ribozymes, are selected when global water chemistry is cooled down. Hence RNA is among the best of the best primordial generic catalysts out there.

And of course the final constraint, which is to be published in Nature, is now known. [ http://www.nature.com/news/bacteria-rep ... cy-1.11446 ] It turned out to be the statistical physics of self replication. [ http://arxiv.org/abs/1209.1179 ] The thermodynamics is such that stabler compounds like DNA and likely PNA, TNA, GNA as well as PAHs (and by my estimate proteins) are too demanding on free energy to replicate.

RNA is, comfortably but perhaps uniquely, situated in a valley of fast enough replication and hydrolysis to make replicators. RNA heat bound is ~ 7 kcal/mol while typical ligation has ~ 10 kcal/mol available, so we are 'set for life' [sic!]. But protein heat bound is ~ 11 kcal/mol and DNA ~ 16 kcal/mol. [p3; my estimate on proteins.]

To return to older results, it has long been suspected that when RNA hits self-replication, the exponential growth of replicating parts of metabolism becomes firmly entrenched as a robust metabolic core. Growth and as seen above replication is materially and energetically "parasitic" on reusing (generic parts, breakdown after use) and recursing (feedback loops) metabolism, so we need all the amplification we can get. Conversely the largest amplification is likely conserved.

In Shoztak's protocells such polymer growth is enough to start darwinian selection on self-assembled lipid membranes that grow and divide under competition over lipid molecules. The largest protocells maximize uptake of free molecules and assimilation of the membranes of other protocells.

Such protocells would likely evolve in hydrothermal vents over subducting plates. There naturally produced phosphates would activate nucleotides which would been taken up and at first retained by hot-cold cycle spontaneous bonding. The same vents would be implicated in related polyphosphate and ATP cofactor metabolic function.

But again new is a proposed shorter pathway from replication to self-replication to genetic replication by way of elucidating early RNA replication machinery. Protocells multiple protogenes need to be "melted", unwound from spontaneous mirror bonding RNA pieces, before ribozymes can replicate.

When genes gets longer you need a directional machinery instead of relying on random directionality. It turns out that the simplest machinery that makes a directional so called "molecular ratchet" is a triplet "code"!

[Technically a transpeptidation tRNA adapter to the chaperone that unwound RNA product after the replicase acted. "Hypothesis. Emergence of Translation as a Result of RNA Helicase Evolution", Zenkin, J Mol Evol 2012.]

I.e. the first genetic code was noise, a nonsense code producing random protein polymers, evolved as it increased cellular fitness. Longer protogenes meant faster growth rates by way of better replication machinery. Further evolution would rapidly fixate a meaningful code to make protein products that were non-poisonous, helped the genetic machinery, helped the early metabolism and were recycled as today. This meant evolution from replication to genetic machinery.

Such a process would very quickly free the protocells from the temperate vent zone, where activated nucleotides and other raw material were available, to become free living autotrophs. Remember that the vent protocell world would have ~ 0.1 million year to get there, because it is the maximum lifetime of typical vents. This was already reasonable, but the shorter genetic machinery pathway is more likely.

The answer is that whatever happens today need not bear any resemblance to what happened 3.5 billion years ago in the primordial soup. We don't have any records from the first few billion years of how life was organized on a chemical level. All the rocks from that age have been recycled back into the interior of the planet.

Organisms trapped in amber or dormant extremeophile organisms in rock, ice, or salt date back almost half a billion years, but nothing on earth dates from the time when we suspect biomolecules first arose in self-replicating structures. We can infer from DNA mutation rates, long-lived species, and other methods what the most likely ancient pathways are, but that doesn't get us very far back and it's all far too uncertain for us to say with any certainty how the first self-organizing biomolecules did their thing.

I beg to differ. As I have mentioned, whole genome methods have elucidated life all the way back to the pure RNA world, mainly since 2010. The genome and other parts of the directly inherited cellular machinery certainly originated very early.

- The whole genome protein fold results is a self-clocked by fold clock proxy model reaching back to before the domain evolution all the way back to the first RNA-protein world. [See my earlier comment.]

Wow!!! In my view, this is huge. All of this provides a potential pathway for ADP/ATP. Now if this could be done with Fe rather than Cu, and if it didn't require the high energy of UV, then we could break out the champagne glasses. Pretty amazing!!!

Wow!!! In my view, this is huge. All of this provides a potential pathway for ADP/ATP. Now if this could be done with Fe rather than Cu, and if it didn't require the high energy of UV, then we could break out the champagne glasses. Pretty amazing!!!

UV was not a problem as such in a non-oxygenated atmosphere (no ozone), at least for most UV energies. It would likely reach down to the many surface vents available. Protocells could develop in pores, or originally as lipid covered pores, in the vent "sponge like" material.

The problems is IMO mainly two:

- purine production.

- surface vents that were also associated with subduction (making and releasing phosphates).

Perhaps also reaction rates, which rejected Wächterhäusers surface metabolism in some -08 paper. I hear the rates are enough for vent hypothesis (according to the vent enthusiasts), the enthalpic enzyme selection paper shows that classically estimated rates are _way_ too low so the rates goes in the right direction - but I still want to see the whole enchilada.